Alzheimer's disease (AD) is a significant health problem, and an economic problem as well, in modern society. It is a degenerative disease of the central nervous system; clinical symptoms include progressive memory loss and decline in cognitive functions. Typically, the onset of AD is in the middle to late stages of human life. Late onset AD occurs at ages greater than 60 years while the symptoms of early onset AD appear in affected individuals between 30 and 60 years of age. At the histological level, Alzheimer's disease is characterized by such pathological features as amyloid plaques and intraneuronal neurofibrillary tangles [Sherrington et al. (1995) Nature 375:754-760].
Several genetic loci have been implicated in AD, which appears to be complex with respect to its etiology. The 112Cys to Arg allele of ApolE (Apolipoprotein E) is associated with a significant proportion of the late onset AD cases [Strittmatter et al. (1993) Proc. Natl. Acad. Sci. USA 90:1977-1981; Saunders et al. (1993) Neurology 43:1467-1472]. Mutations in the .beta.-amyloid precursor protein gene (.beta.APP) have been associated in certain families (&lt;3%) with AD onset prior to 65 years of age [See, e.g., Goate et al. (1991) Nature 349:704-706]. A third locus associated with AD is the stm-2 locus on chromosome 1; this gene determines the presenilin protein. Another locus (AD3 on chromosome 14q24.3), which functions as an autosomal dominant locus, may account for up to 70% of the cases of early onset AD [Schellenberg et al. (1992) Science 258:1445-1453]. Sherrington et al. (1995) supra has described five different missense mutations in a novel gene called s182, which mutations are associated with early onset AD. Pedigree studies suggested that these mutations confer an autosomal dominant AD phenotype. Sequence analysis of the deduced amino acid sequence indicates that the protein product of this gene is likely to be an integral membrane protein despite the absence of an obvious signal peptide sequence and a dearth of potential glycosylation sites. The human S182 protein shares significant amino acid homology with the Caenorhabditis elegans spe-4 gene product, which has been shown to function in spermatogenesis in the nematode [L'Hernault et al. (1992) J. Cell Biol. 119:55-69].
To date, conclusive diagnosis has generally required histological analysis of brain tissue, after death. In view of the invasiveness of sampling of brain tissue and the desirability of conclusively diagnosing human disease during life, there is a long felt need in the art for a noninvasive diagnostic test for Alzheimer's disease.